Prostanoid EP4 receptor is a G protein-coupled receptor that mediates the actions of prostaglandin E2 (PGE2) and is characterized by the longest intracellular C terminus loop when compared to other prostanoid receptors. The EP4 receptor is one of four receptor subtypes of prostaglandin E2 receptors. Mainly, EP4 receptors couple to G proteins and mediate elevations in cyclic-adenosine monophosphate (“cAMP”) concentration, although they do participate in other pathways as well. There are some redundancies in function between EP2 and EP4 receptors. For example, both receptors induce PGE2-mediated RANKL through cAMP. However, EP2 is involved in cumulus expansion in ovulation and fertilization, whereas EP4 regulates closure of the ductus arteriosus. Expression of EP4 receptors is controlled by various physiological and pathophysiological processes as these receptors participate in ovulation and fertilization, induce bone formation, protect against inflammatory bowel disease, facilitate Langerhans cell migration and maturation and mediate joint inflammation in a model of collagen-induced arthritis, among others.
PGE2 represents the major prostaglandin in human and rat skin (Jonsson and Ängg{dot over (a)}rd, Scand J Clin Lab Invest, 29, 289-296, 1972; Jouvenaz et al, Biochim Biophys Acta, 202, 231-234, 1970). Studies of keratinocyte proliferation modulation indicate that PGE2 is a growth-promoting autocoid for the epidermis, and that epidermal PGE2 synthesis may be enhanced in wound healing and disease states characterized by the disruption of epidermal continuity (Pentland and Needleman, J Clin Invest, 77(1), 246-251, 1986). Moreover, endogenous PGE2 has been shown to modulate human skin keratinocyte differentiation (Evans et al, Prostaglandins Leukot Essent Fatty Acid 49: 777-781, 1993). The observed differential expression of EP4 receptor mRNA in fetal and adult rabbit skin before and after wounding, with EP4 mRNA up-regulation in fetal skin, supports a role for PGE2 in the regulation of intracellular signal transduction via binding to EP4 receptor during fetal wound repair (Li et al, Arch Otolaryngol Head Neck Surg 126, 1337-1343, 2000). At least the preceding findings indicate that PGE2 production is essential for cutaneous wound healing.
Skin blemishes such as flesh wounds, scars and wrinkles can occur on any area of the body. Scarring may occur in all parts of the adult body, following local or systemic traumas such as mechanical injury, surgery, burn, radiation and poisoning, and represents a failure of homeostatic processes to restore normal structure at the wound sites. Wrinkles occur for a variety of reasons and are a common sign of aging. Both scars and signs of aging can typically be considered undesirable.
Accordingly, an agent that safely and effectively treats or prevents such skin blemishes is highly desirable.